Binding Thermodynamics and Kinetics Calculations Using Chemical Host and Guest: A Comprehensive Picture of Molecular Recognition

Abstract

Understanding the fine balance between changes of entropy and enthalpy and the competition between a guest and water molecules in molecular binding is crucial in fundamental studies and practical applications. Experiments provide measurements. However, illustrating the binding/unbinding processes gives a complete picture of molecular recognition not directly available from experiments, and computational methods bridge the gaps. Here, we investigated guest association/dissociation with β-cyclodextrin (β-CD) by using microsecond-time-scale molecular dynamics (MD) simulations, postanalysis and numerical calculations. We computed association and dissociation rate constants, enthalpy, and solvent and solute entropy of binding. All the computed values of kon, koff, ΔH, ΔS, and ΔG using GAFF-CD and q4MD-CD force fields for β-CD could be compared with experimental data directly and agreed reasonably with experiment findings. In addition, our study further interprets experiments. Both force fields resulted in similar computed ΔG from independently computed kinetics rates, ΔG = −RT ln(kon·C0/koff), and thermodynamics properties, ΔG = ΔH − TΔS. The water entropy calculations show that the entropy gain of desolvating water molecules are a major driving force, and both force fields have the same strength of nonpolar attractions between solutes and β-CD as well. Water molecules play a crucial role in guest binding to β-CD. However, collective water/β-CD motions could contribute to different computed kon and ΔH values by different force fields, mainly because the parameters of β-CD provide different motions of β-CD, hydrogen-bond networks of water molecules in the cavity of free β-CD, and strength of desolvation penalty. As a result, q4MD-CD suggests that guest binding is mostly driven by enthalpy, while GAFF-CD shows that gaining entropy is the major driving force of binding. The study deepens our understanding of ligand–receptor recognition and suggests strategies for force field parametrization for accurately modeling molecular systems.

Insights into Noncovalent Binding Obtained from Molecular Dynamics Simulations

“…in agreement with [88]. The sensitivity of the binding free enthalpy with regard to this choice turned out to be very small which can also be seen from the distribution of distances, also shown in Fig.…”

“…shows the time series of the distance between the center of the α ‐cyclodextrin molecule and that of the 1‐butanol molecule. The discrimination between bound and unbound states was based on a cut‐off distance of 0.75 nm in agreement with . The sensitivity of the binding free enthalpy with regard to this choice turned out to be very small which can also be seen from the distribution of distances, also shown in Fig.…”

“…The average residence time of the guest molecule inside the host is usually shorter than an average experimentally determined survival time because in an experiment several short‐term events are likely to be missed. Therefore, only bound/unbound periods that lasted longer than 1 ns were counted as one bound/unbound event, which is in line with .…”

The Role of Displacing Confined Solvent in the Conformational Equilibrium of β-Cyclodextrin

“…Previous work has also noted the existence of these two conformations in explicit solvent with different force fields and water models. 37,45,67 The displacement of water from the interior of the cavity plays a critical role in the reorganization mechanism of β-CD from open to closed conformations. Water molecules enclosed in the host cavity experience unfavorable free energies relative to bulk water.…”

The Role of Displacing Confined Solvent in the Conformational Equilibrium of β-Cyclodextrin

“…Due to its simple molecular structure and the availability of accurate experimental binding affinities, β-CD is a popular host molecule for the study of molecular recognition. 34,[37][38][39][40][41][42][43][44][45][46][47][48] Recent work on β-CD host-guest systems has demonstrated the importance of incorporating reorganization and water expulsion effects into implicit solvent binding affinity models. 48 In these studies, implicit solvent hydration sites were developed to account for the thermodynamically unfavorable waters inside the cavity of the apo β-CD host, that when displaced by a ligand during the binding process result in an increased binding affinity.…”